Preparation of tertiary-butyl aryl ethers

ABSTRACT

Tertiary-butyl aryl ethers are prepared by reacting the corresponding phenol or phenolic compound with N,Ndimethylformamide di-t-butyl acetal under basic conditions. The preparation of substantially pure N,N-dimethylformamide di-tbutyl acetal by the acid-catalyzed trans-acetalization of N,Ndimethylformamide dimethyl acetal with t-butanol is also described.

United States Patent [191 Leimgruber et al.

[451 Nov. 18, 1975 i 1 PREPARATION OF TERTIARY-BUTYL ARYL ETHERS [75]Inventors: Willy Leimgruber, Montc'lair;

Ernest Mohacsi, Nutley, both of NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Jan. 16, 1974 [21] Appl. No.: 433,643

Related US. Application Data [62] Division of Ser. No. 208,952, Dec. 16.1971,

abandoned.

[52] US. Cl. 260/584 C; 260/584 R [51] Int. Cl. C07C 91/02; C07C 93/02;

[58] Field of Search 260/584 R, 584 C [56] References Cited UNITEDSTATES PATENTS 3,239,519 3/1966 Winberg 260/584 R X PrimaryExaminefePaul F. Shaver Attorney, Agent, or FirmSamuel L. Welt; BernardS. I

Leon; William G. Isgro 3 Claims, No Drawings BACKGROUND OF THE INVENTIONConventional methods of the prior art for the preparation of t-butylaryl ethers, for example, those described by D. R. Stevens, J. Org.Chem, 20, 1232 (1955) and the references cited therein, require strongacid catalysis, which in addition to causing certain compounds todecompose or rearrange, results in the obtainment of the desired t-butylethers in very poor yields (l-33 percent). The process of the inventionsubstantially increases the yield of the desired t-butyl aryl ethers,mainly because the reaction is carried out in the presence of a basicreagent, which does not cause rearrangement or decomposition of theproduct.

Impure N,N-dimethylformamide di-t-butyl acetal has been previouslyprepared and described by Arnold et al., in Z. Arnold and M. Komilov,Collection Czechoslov. Chem. Commun. 29, 645651 (1964). It has now beenfound unexpectedly, (cf. Collection Czechoslov. Chem. Commun." 29, 645[1964]), that through trans-acetalization of N,N-dimethylformamidedimethyl acetal with t-butanol, N,N-dimethylformamide di-t-butyl acetalcan be prepared which is substantially pure.

BRIEF SUMMARY OF THE INVENTION The invention relates to the preparationof t-butyl aryl ethers by a process which comprises reacting thecorresponding phenol or phenolic compound with N,N-dimethylformamidedi-t-butyl acetal under basic conditions.

In another aspect, the invention relates to the preparation ofN,N-dimethylformamide di-t-butyl acetal by a process which comprises theacid-catalyzed trans-acetalization of N,N-dimethylformamide dimethylacetal with t-butanol, involving the simultaneous removal of the formedmethanol, whereby N,N-dimethylformamide di-t-butyl acetal is obtained.

In yet another aspect, the invention relates to substantially pureN,N-dimethylformamide di-t-butyl acetal.

DETAILED DESCRIPTION OF TI-IE INVENTION In one aspect, the inventionrelates to a process for the preparation of aromatic compounds having atleast one t-butoxy group on the aromatic nucleus which comprisesreacting a phenolic compound with N,N- dimethylformamide di-t-butylacetal under basic conditions.

This process aspect of the invention can be particularly illustrated byReaction Scheme I, which follows:

REACTION SCHEME I T O-C-CH CH l CH N-C H 11 CH3 (1H3 O-CII-CH CH O-C- CHCH3 (III) wherein is the aromatic nucleus of a hydrocarbon radical, suchas, for example, phenyl, naphthyl, phenanthrenyl, tet rahydronaphthyl,tetra-, hexa-' and octa-hydrophenanthrenyl, 2,6-methano-3-benzazocinyl,10,4aimino-ethanophenanthrenyl,4al-I-8,9c-iminoethanophenantro[4,5-b,c,d]furyl, or the like, and n is awhole number from 1 to 3. It is to be understood that the hydrocarbonradical can be unsubstituted or can bear one or more substituents, suchas, for example, acetoxy, halogen, hydroxy, acylamido, lower alkoxy,lower alkyl, nitro, carboxy or the like-Furthermore, it is to beunderstood that the hydrocarbon radical can contain one or more heteroatoms, such as, for example, nitrogen, oxygen, sulfur or the like.

As used herein, the term lower alkyl denotes a straight or branchedsaturated hydrocarbon containing 1 to 5 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl andthe like; preferred is methyl. The term lower alkoxy denotes an alkylether group in which the lower alkyl group is as described above, forexample, methoxy, ethoxy, propoxy, pentoxy, and the like; preferred ismethoxy.

- The term halogen denotes all the halogens, i.e., bromine, chlorine,fluorine and iodine; preferred are chlorine and bromine. The term acyldenotes an alkanoyl group derived from an aliphatic carboxylic acid of 1to 7 carbon atoms, for example, formyl, acetyl, propionyl and the like;and an aroyl group derived from an aromatic carboxylic acid, such asbenzoyl and the like.

Exemplary of the phenolic hydrocarbons which can be utilized in theprocess of the invention are: phenol, naphthol,3-hydroxy-N-methylmorphinan, 3-hydroxy- N-formylmorphinan,3-hydroxymorphinan, morphine, rnand p-cresol, p-aminophenol,o-nitrophenol, 2,4,6-trinitrophenol, p-acetamidophenol, thymol, 2,6-di-t-butyl-4-methylphenol, 2-hydroxy-4-isopropyltoluene, guaiacol,eugenol, pyrocatechol, resorcinol, hydroquinone,2,4,6-trinitroresorcinol, pyrogallol, phloroglucinol, o-, niandp-bromophenol, and the like.

Exemplary of the products of formula III are: (+)-3-tbutoxy-N-methylmorphinan, ()-3-t-butoxy-N-methylmorphinan,(+)-3-t-butoxymorphinan, 3-t-butoxy-7,8- didehydro-4,5a-epoxy- 17-methylmorphinan-6a-ol, tbutyl phenyl ether, t-butyl l-naphthyl ether,o-, mand p-t-butoxytoluene, 1-tbutoxy-2-nitrobenzene,l-tbutoxy-3-nitrobenzene, 1-t-butoxy-4-nitrobenzene,l-tbutoxy-2,4,6-trinitrobenzene, l-bromo-2-tbutoxybenzene,l-bromo-3-t-butoxybenzene, 1-bromo-4-tbutoxybenzene,1,2-di-t-butoxy-benzene, l-t-butoxy-Z- methoxybenzene,1,3-di-t-butoxy-4-n-hexylbenzene, l ,4-di-t-butoxybenzene,1,2,3,-tri-t-butoxybenzene, l,3,5-tri-t-butoxybenzene,p-t-butoxy-acetanilide and the like.

In the process of the invention, the phenolic compound is reacted withN,N-dimethylformamide di-tbutyl acetal at an elevated temperature; thatis, at a temperature in the range of between about 80C. and the refluxtemperature of the reaction mixture. Preferably, the reaction is carriedout at reflux temperature of the reaction mixture.

N,N-Dimethylformamide di-t-butyl acetal is reacted with the phenoliccompound in equimolar or greater than equimolar ratios; preferably, anexcess of N,N- dimethylformamide di-t-butyl acetal is utilized, forexample, from about 2 to about 5 moles of acetal for each mole ofphenolic compound. Since an excess of N,N- dimethylformamide di-t-butylacetal is utilized in the process of the invention, it can also act as asolvent for 4 the phenolic compound. Thus, the utilization of additionalinert solvents is not generally required but is not precluded.

The reaction of the phenolic compound and N,N- dimethylformamidedi-t-butyl acetal is carried out under basic conditions. SinceN,N-dimethylformamide di-t-butyl acetal is basic, the reaction mixtureis maintained on the basic side without any additional manipulativesteps and/or added substances. After the reaction is completed, thereaction product, i.e., the desired aromatic compound having at leastone t-butoxy group in its aromatic nucleus, can be separated from thereaction mixture by conventional methods as, for example, filtration,crystallization, distillation or the like.

Since the phenolic starting material may possess, in addition tohydroxy, various other groups which can react with N,N-dimethylformamidedi-t-butyl acetal, it may be desirable to protect such groups. Acarboxylic acid group can be esterified utilizing conventional methods.When and if desired, the ester group can be converted again to thecarboxylic acid by base catalyzed hydrolysis. A secondary amine groupcan be protected by an electron-withdrawing group such as formyl, acetyland the like, utilizing known procedures. When and if desired, theelectron-withdrawing group can be removed by base catalyzed hydrolysis,for example, utilizing sodium hydroxide. The hydroxy group of an allylicalcohol can be acetylated by known procedures. When and if desired, theprotecting group can be removed by base catalyzed hydrolysis.

In the alternative, it is possible to allow N,N-dimethylformamidedi-t-butyl acetal to also react with a carboxy group to form thecorresponding t-butyl ester.

In another aspect, the invention relates to the preparation ofsubstantially pure N,N-dimethylformamide di-t-butyl acetal by a processwhich comprises the acidcatalyzed trans-acetalization ofN,N-dimethylformamide dimethyl acetal with t-butanol.

More particularly, the N,N-dimethylformamide dimethyl acetal istrans-acetalized with t-butanol in the presence of a catalytic amount ofweak acid, which preferably is a sterically highly hindered phenol suchas 2,4,6-tri-t-butylphenol or 2,6-di-t-butylphenol. The catalytic amountmay be in the range of about 0.01 mole to about 0.1 mole per mole ofN,N-dimethylformamide dimethyl acetal; most preferred is 0.01 mole.Conveniently, as excess of t-butanol is utilized. Such excess maycomprise from about 2 to about 4 moles of t-butanol per mole ofN,N-dimethylformamide dimethyl acetal. The trans-acetalization iscarried out at a temperature in the range of about 1 l0 to about 1 15.The methanol formed in the trans-acetalization reaction is removed fromthe reaction mixture by continuous distillation.

The t-butyl aryl ethers produced by the process of the invention areuseful and generally known compounds. For example, B-naphthyl t-butylether is a useful compound for perfumes. p-t-Butoxy-acetanilide hasshown potent and long-lasting antipyretic-analgesic activity. Thet-butyl aryl ethers are also useful as intermediates in the preparationof known and useful end products.

The following examples further illustrate the invention. Alltemperatures are in degrees Centigrades, unless otherwise mentioned.

EXAMPLE 1 Preparation of (+)-3-t-butoxy-N-methylmorphinan from(+)-3-hydroxy-N-methylmorphinan A mixture of 12.0 g. of(+)-3hydroxy-N-methylmorphinan and 19.0 g. of N,N-dimethylformamidedi-tbutyl acetal was heated at 100-110 for 2 hours under an atmosphereof nitrogen, during which time a clear red solution was obtained. Thetwo additional 9.5 g. portions of N,N-dimethylformamide di-t-butylacetal were added successively at 2 hour intervals,and heating wascontinued for an additional 6 hours. The excess of reagent was removedunder vacuum, and the residue was diluted with ethyl acetate (300 ml.).The resulting solution was washed successively with 2N sodium hydroxide(2 X 60 ml.) and water. The organic phase was dried and evaporated, andthe residue was distilled to give 8.0 g. (55 percent) of pure(+)-3-t-butoxy-N- methylmorphinan, bp l85200/0.l mm, [111 50.0 (c 0.98,MeOH).

Analysis Calcd. for C H NO (313.49): C, 80.46; H, 9.97; N, 4.47. Found:C, 80.57; H, 9.96; N, 4.68.

EXAMPLE 2 Preparation of (+)-3-t-butoxy-N-methylmorphinan D-tartratehydrate A mixture of 8.7 g. of (+)3-t-butoxy-N-methylmorby filtrationand recrystallized from isopropanol to give 5 9.1 g. of pure ()3t-butoxyN-methylmorphinan 'L- I tartrate hydrate, mp l05107 (dec. [011 36.3"-(c- -0.99, MeOH).

Analysis Calcd. for C H NO.C H O .H O(481.55): C, 62.35; H, 8.16; N,2.91. Found: C, 62.20; H,'8.13;

phinan, 4.1 g. of D-tartaric acid and 25 ml. of isopropa- EXAMPLE 3Preparation of ()-3t-butoxy-N-methylmorphinan from()-3hydroxy-N-methylmorphinan A mixture of 11.3 g. of(-)-3-hydroxy-N-methylmorphinan and 18.1 g. of N,N-dimethylformamidedi-tbutyl acetal was heated at 1001 10 for 2 hours under nitrogen,during which time a clear red solution was obtained. Then two additional9.0 g. portions of N,N- dimethylformamide di-tbutyl acetal were addedsuccessively at 2hour intervals, and heating was continued for anadditional 6 hours. The excess of reagent was removed under vacuum, andthe residue was diluted with ethyl acetate (300 ml.). The resultingsolution was washed successively with 2N sodium hydroxide (2 X 60 ml.)then with water. Thereafter, the organic phase was dried and evaporatedand the residue was distilled to give 8.1 g. (59 percent) of(')-3-t-butoxy-N-methylmorphinan, bp 180200/0.1 mm, [0:] 49.3 (c 0.93,MeOH).

Analysis Calcd. for C H NO (313.49): C, 80.46; H, 9.97; N, 4.47. Found:C, 80.24; H, 9.88; N, 4.77.

EXAMPLE 4 Preparation of ()-3t-butoxy-N-methylmorphinan L-tartratehydrate A mixture of 7.1 g. of ()-3-t-butoxy-N-methylmorphinan, 3.4 g.of L-tartaric acid, and 25 m1. of hot iso EXAMPLE 5 Preparation of(+)-3-methoxymorphinan (l-)-3Methoxy-N-formylmorphinan, 78.4 g. wasdissolved in 2 l. of methanol and 800 ml. of 2.5N aqueous sodiumhydroxide was added. After this mixture has I been heated under refluxfor 24 hours, the methanol was removed under reduced pressure and theresulting aqueous suspension was extracted with methylene chloride (3 X750 ml.). The combined methylene chloride extracts were washed withwater and dried. Removal of the solvent under vacuum yielded 63.9 g.percent) of crude (+)-3-methoxymorphinan. A sample of this compound wasdistilled, bp 148-150./0.05 mm,

[01],, 3l.97 (c 1.1, MeOH).

Analysis Calcd. for C H NO (257.35): C, 79.33; H, 9.01; N, 5.54. Found:C, 79.20; H, 8.81; N, 5.58.

EXAMPLE 6 Preparation of (+)-3-hydroxymorphinan from(+)-3-methoxymorphinan v (+)-3-Methoxymorphinan hydrobromide, 10.0 g. in50 ml. of 48 percent HBr was refluxed for 2 hours. The cooled solutionwas made basic with concentrated ammonium hydroxide. The precipitate wasfiltered and dried to give 7.2 g. percent) of crude (+)-3-hydroxymorphinan. A sample of this compound was recrystallized frommethanol, mp 273274, [(11 38.5 (c 1.0, MeOH).

Analysis Calcd. for C H NO (243.33): C, 78.97; H, 8.70; N, 5.76. Found:C, 79.24; H, 8.68; N, 5.92.

EXAMPLE 7 Preparation of (+)3hydroxy-N-formylmorphinan from(+)-3-hydroxymorphinan A solution of 2.0 g. of (+)-3-hydroxymorphinan ina mixture of 3.5 ml. of formic acid and 2.2 ml. of triethylamine washeated under reflux for 16 hours. The reaction mixture was concentratedunder reduced pressure and the residue vwas dissolved in chloroform andwashed successively with dilute hydrochloric acid and water. Thechloroform solution was dried and concentrated to give 1.8 g. (81percent) of crude (+)-3- hydroxy-N-formylmorphinan. A sample of thiscompound was distilled, bp 240242/0.25 mm, [011 184 (c 1, MeOH).

Analysis Calcd. for C H NO (271.34): C, 75.21; H, 7.80; N, 5.16. Found:C,75.14; H, 7.71; N, 5.23.

EXAMPLE 8 Preparation of (+)-3-t-butoxy-N-formylmorphinan from(+)-3hydroxy-N-formylmorphinan A mixture of 3.0 g. of(+)-3-hydroxy-N-fonnylmorphinan and 9.0 g. of N,N-dimethylformamidedi-t-butyl acetal was heated under reflux for 5 hours, during which timea dark solution was obtained. The excess of dium hydroxide (3 X 20 ml.)and water. The ethyl acetate solution was dried and concentrated undervacuum to give 1.1 g. (30 percent) of crude (+)-3-t-butoxy-N-formylmorphinan. A sample of this compound was distilled, bp l70175/0.2mm.

Analysis Calcd. for C H NO (327.44): C, 77.02; H, 8.93, N, 4.28. Found:C, 76.66; H, 9.12; N, 4.46.

EXAMPLE 9 Preparation of (+)-3-t-butoxymorphinan from(+)-3-t-butoxy-N-formylmorphinan 0.9 g. of (+)-3-t-ButoxyN-formylmorphinan was dissolved in 21 ml. of methanol and 7 ml. of 2.5Naqueous sodium hydroxide was added. After this mixture had been heatedunder reflux for 48 hours, the methanol was removed under reducedpressure and the resulting aqueous suspension was extracted withmethylene chloride (60 ml.). The combined methylene chloride extractswere washed with water and dried. Removal of solvent under vacuumyielded 0.8 g. (97 percent) of crude (+)-3-t-butoxymorphinan. The base(800 mg.) on addition with D-tartaric acid (400 mg.) in ethanol (7 ml.)afforded 680 mg. of salt, which after two recrystallizations fromethanol yielded 540 mg. (46 percent) of pure (+)-3-butoxymorphinanD-tartrate, mp 207-208 (dec.), [0:] 37.4 (c 1.05, MeOH).

Analysis Calcd. for C H NO.C H O (449.52): C, 64.12; H, 7.85; N, 3.13.Found: C, 63.99; H, 7.68; N, 3.37.

EXAMPLE 10 I Preparation of O -diacetylmorphine from morphine 25.6 g. ofMorphine. were stirred with acetic anhydride 120 ml.) and pyridine (120ml.) at room temperature for 48 hours. The excess of acetic anhydrideand pyridine were removed at 30 under vacuum and to the residue, water(200 ml.) was added. The aqueous suspension was made basic with sodiumbicarbonate and was extracted with chloroform (3 X 200 ml.). Thecombined extracts were dried, and after evaporation of the chloroform,the residue was recrystallized from ethyl acetate to give 28.6 g. (86percent) of O -diacetylmorphine, mp 172-l74.

EXAMPLE 1 1 Preparation of O -monoacetylmorphine from O-diacetylmorphine A solution of 28.6 g. of O -diacetylmorphine inethanol (390 ml.) was treated with concentrated aqueous solution ofhydroxylamine hydrochloride (10.4 g.). The reaction mixture was stirredat room temperature for 15 minutes during which period the hydrochlorideof monoacetylmorphine crystallized. The solvent was removed underreduced pressure, and to the residue was added water (200 ml.). Thesolution was made basic with concentrated ammonium hydroxide andextracted thoroughly with chloroform (3 X 200 ml. Evaporation ofchloroform and crystallization of the residue from ethyl acetate (500ml.) gave 25.4 g. (100 percent) of O -monoacetylmorphine, mp 188190EXAMPLE 12 Preparation of3-t-butoxy-7.8-didehydro-4,5a-epoxy-17-methylmorphinan-6a-oltrans-3-dimethylamino-Z-propenoic acid ester from o -monoacetylmorphineand N,N-dimethylformamide di-t-butyl acetal A mixture of 23.0 g. of o-monoacetylmorphine and 32.0 g. of N,N-dimethylformamide di-t-butylacetal was heated at l00ll0 for 30 minutes under nitrogen, during whichtime a clear solution formed. Then an additional two'l6.0 g. portions ofN,N-dimethylformamide di-t-butyl acetal were added successively in 2hour intervals and the heating was continued for an additional 6 hours.The excess of reagent was removed under reduced pressure and the residuewas dissolved in ethyl acetate (500 ml.) and washed successively with 2Nsodium hydroxide (3 X ml.) and water (70 ml.). The ehtyl acetatesolution was dried and concentrated to give 15.5 g. (50 percent) ofcrude 3-t-butoxy-7,8- didehydro-4,5oz-epoxy-l 7-methylmorphinan-6a-oltrans-3-dimethylamino-2-propenoic acid ester. A sample of this compoundwas distilled, bp 220225/0.1

Analysis Calcd. for C H N O (438.57): C, 71.20; H, 7.82; N, 6.39. Found:C, 71.04; H, 8.02; N, 6.46.

EXAMPLE 13 Preparation of 3-t-butoxy-7 8-didehydro-4,5 a-epoxyl7-rnethylmorphinan-6a-ol from 3-t-butoxy-7,8-didehyd ro-4,5 a-epoxy- 17-methylmorphinan-6a-ol trans-3-dimethylamino-2-propenoic acid ester15.0 g. of 3-t-Butoxy-7,8-didehydro-4,5a-epoxy-17- methylmorphinan-6a-oltrans-3-dimethylamino-2- propenoic acid ester was dissolved in 600 ml.of ethanol and 280 ml. of 2N aqueous sodium hydroxide were added. Afterthis mixture had been heated under reflux for 24 hours, the ethanol wasremoved under reduced pressure and the resulting aqueous suspension wasextracted with chloroform (3 X 300 ml.). The combined organic layerswere washed with 2N aqueous sodium hydroxide ml.), then with water ml.)and dried. The solvent was removed under vacuum and the residuedistilled (bp 220230/0.2 mm.) to give 10.69 g. (92 percent) of3-t-butoxy-7,8-didehydro-4,5aepoxy-l7-methylmorphinan-6oz-ol, [a] 79.8(c 0.8, MeOH).

Analysis Calcd. for C H NO (341.46): C, 73.87; H, 7.97; N, 4.10. Found:C, 73.70; H, 8.14; N, 3.93.

EXAMPLE 14 Preparation of 3 -t-buto xy-7 ,8-didehydro-4, 5a-epoxy-17-methylmorphinan-6a-ol D-tartrate diethanolate from 3-t-butoxy-7 8-didehydro-4,5 a-epoxyl 7-methy1morphinan-6a-ol 10.9 g. of3-t-Butoxy-7,8-didehydro-4,5a-epoxy-17- methylmorphinan-6a-o1 wasdissolved in 25 ml. of hot ethanol and a hot solution of D-tartaricacid, 4.6 g., in 25 ml. of ethanol was added. The tartrate was allowedto crystallize and was separated by filtration. Recrystallization fromethanol ml.) gave 14.8 g. (82 percent) of3-t-butoxy-7,8-didehydro-4,5a-epoxy-17- methylmorphinan-6a-ol D-tartratediethanolate, mp 105106(dec.), [c21 -28.2 (c 1.18, MeOH).

EXAMPLE 15 Preparation of morphine from 3-t-butoxy-7 ,8-didehydro-4,5a-epoxyl 7-methylmorphinan-6a-ol 120 mg. of3-t-Butoxy-7,8-didehydro-4,5a-epoxy-17- methylmorphinan-6a-ol in INaqueous hydrochloric acid was stirred at room temperature for 17 hours.The solution was made basic with concentrated ammonium hydroxide and theproduct was collected by filtration. Recrystallization from ethanol gave90 mg. (90 percent) of morphine, mp 247249. Its mixed melting point withan authentic sample was undepressed.

EXAMPLE 16 Preparation of methoxymethylmorphine from morphine 18.0 g. ofA suspension of sodium morphine and 60 ml. of chloroform (dry) werestirred at room temperature while chloromethyl methyl ether (5.1 g.)

was added dropwise over a period of 30 minutes. The

Analysis Calcd. for C H NO (329.37): C, 69.28; H, 7.04; N, 4.25. Found:C, 69.58; H, 7.01; N, 4.26.

EXAMPLE 17 Preparation of 7,8-didehydro-4,5 a-epoxyl 7-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy )-3-methoxymethylmorphinan frommethoxymethylmorphine and 2,2,2-trichloroethyl chloroformate 11.0 g. of2,2,2-trichloroethyl chloroformatewas added dropwise to a stirredsolution of 12.2 g. of me-- thoxymethylmorphine in 130 m1. of drypyridine at ice bath temperature over a period of 45 minutes. Then, thereaction mixture was stirred at room temperature for minutes. Thepyridine was removed under vac uum and the residue was dissolved inwater (60 ml.). The aqueous solution was made basic by concentratedammonium hydroxide and extracted with chloroform (3 X 80 ml.). Thechloroform solution was washed with water, dried, and evaporated. Theresidue was recrystallized from ethyl acetate-hexane to give 11.5 g. (62percent) of 7,8-didehydro-4,5a-epoxy-l7-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy)-3-methoxyrnethylmorphinan, mp124-125, [01],, -l 64.0 (c 1.10,

MeOH). I

Analysis Calcd. for C H CI NO (504.78): C, 52.47; H, 4.79; N, 2.78.Found: C, 52.63; H, 4.68; N,

EXAMPLE 1 8 Preparation of7,8-didehydro-4,5a-epoxy-17-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy)morphinan-3-olfrom7,8-didehydro-4,5a-ep0xy-17-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy)-3-methoxymethylmorphinan11.1 g. of 7,8-Didehydro-4,5a-epoxy-17-methyl-6a-(2,2,2-trich1oroethy1carbonyldioxy )-3 -methoxymethylmorphinan wasdissolved in 140 ml. of methanoland 220 ml. of 1N aqueous hydrochloricacid was added. After thismixture has been stirred at room temperaturefor 56hours, the solution was made basic with concentrated ammoniumhydroxide at ice bath temperature. The-methanol was then removed underreduced pressure at 36. The resulting aqueous suspension was extractedwith chloroform (3 X 120 ml.). The combined extracts were dried andconcentrated to a residue which was crystallized from ethanol to give8.1 g. percent) of 7,8-didehydro-4,5a epoxy-17-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy)morphinan-3-01, mp l-192, [01],, 168(c 1.19, MeOH).

Analysis Calcd. for C H Cl NO (460.73): C, 52.24; H, 4.38; N, 3.04.Found: C, 52.47; H, 4.32; N, 2.93;

EXAMPLE 19 Preparation of7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-

' diol-6-dimethylcarbamate from 7,8-didehydro-4,5a-epoxy-17-methyl-6a-(2,2,2-trichloroethylcarbonyldioxy)morphinan-3-olEXAMPLE 20 Reaction of 7,8-didehydro-4,5 a-epoxyl 7-methylmorphinan-3,6a-

' diol-6-dimethylcarbamate with N,N-dimethylformamide di-t-butyl acetal'A mixture of 3.4 g; of 7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,60z-diol-6-dimethylcarbamate and 3.4 g. ofN,N-dimethylformamide di-t-butyl acetal was heated at for 4 hours undernitrogen during which time a clear solution was obtained. The excess ofreagent was removed under vacuum and the residue was extracted withether (3 X 40 ml.). The combined ethereal solution was washed with 2Nsodium hydroxide (2 X 30 ml.) then with water and dried. Removal of thesolvent under vacuum yielded 2.31 g. (59 percent) of crude3-t-butoxy-7,8-didehydro-4,5a-epoxy-17- methylmorphinan-6a-oldimethylcarbamate. In a previous run, a sample of this compound wasdistilled, bp

19010.22 mm., [02],, -137.8 (c 1.09, MeOH).

11 I 12 Analysis Calcd. for C H N O (412.49): C, 69.88; for 3 hoursunder nitrogen, during which time a clear H, 7.82; N, 6.79. Found: C,69.98; H, 7.93; N, 6.99;. solution was obtained. Then an additional 5.1g. of N,N-dimethylformamide di-t-butyl acetal was added,

EXAMPLE 1 w and the heating was Continued for 2 hours. The cooledl-lyrolysis of g 5 reaction mixture was diluted with ether (300 ml.) and3 t-butoxy-7,8-didehydro-4,5a-epoxy-l7-methylmorwashed successively with2N sodium hydroxide (2 X- phinan-6a-ol dimethylcarbamate 150 ml.) andwater (2 X 150 ml.). The ethereal solution v dried and concentrated togive 08 g. (16 percent) 2.2 g. of 3-t-Butoxy-7,8-d1dehydro-45a-epoxy-l7- was t of crude t-but l l-na th 1 ether which after Kuelrohr methylinorphmanba-ol dlmethylcarbamate was ch87 1O distillation(O 5 mm l -lg) afforded 0 45 g -(9 perc ent) of solved in 14 ml. ofehtanol, and 2.0 g. of potassium hyb l 1 h droxide in 15 ml. of ethanolwas added. After this mixf g f 200 27 c 83 96 H ture had been heatedunder reflux for 16 hours, the eth- 8 6 8 2 anol was removed undervacuum and the resulting arlqggousl- )su iplensiholn gas ex-trlactedwith chLorofor$ 15 EXAMPLE m.. e c oro orm so utionwas was ed wi Iwater, dried and removal of the solvent under vacuum Prepdranon of f gzg dl't'butyl yielded 1.9 g. 100 percent) of crude 3-t-but'oxy 7f8-didehydro-4,5a-epoxy-17 rfietliylmomhinam6fi oll""" 59.5 g. ofN,N-Dimethylformamide dimethyl acetal and 147 ml. of dry t-butanol werecombined in a three- EXAMPLE 22 2O necked flask (250 ml), fitted with athermometer, Preparation of 3,3, 6a, I magnetic stirrer, nitrogeninletand a 33 X 1.9 cm. sil- 6a -dicarbonyldioxybis-7,8-didehydro4,5a-epoxy-17 vered.vacuum-jacketed Goodloe column which wasmethylmorphinan equipped with a 'refluxfcontrolled takeoff distilling Amixture of 2.0 g. of 7.8-didehydro 4,5a-epoxy-17- 25 head" gndemgmixmrewas heated at reflux for 1 hour Then, 300 mg. of 2,4,6-tri-t-butylphenol was added to 2:2 2 53 2??? g t fg figffiggxggg g gfi Lthe solution." The reaction mixture was heated at butyl acetal washeated at reflux temperature under ni- 2 for F f PE at g trogen for 2hours. The excess-ot reag'en-t'wasremoved ga 21 z g co under vacuum andthe residue was triturated with ether er m O utano was a e to e.reactlon (2 X 20 ml) The combined ethereal S 01 utio n was mixture andthe removal of methanol was continued as X w al oy/e for an additional42 hours to afford 64 ml. of dism i s l f ggggg 2;3 i 35222 81 32:tillate. Distillation of the crude product with a similar, vacuumyielded 150 g (97 a crude 3+ but smaller column.(20 X 1.4 cm.) gave thefollowing butoxy7,8-didehydro-4,5a-epoxy l7-methylmorphi- 35' fractions:nan-6a-ol dimethylcarbamate. The ether insoluble residue was extractedwith hot ethyl acetate- Removal of Fracfio" weight Bmng alcanalysis thesolvent under vacuum and crystallization of the res- 1 18.1 g. 34-37770mm Hg MeOl-l and t-BuOH n 0 idue from ethyl acetate gave 360 mg. (13percent) of 2 9- 9 /40 mm Hg gzff gggi g 3,3, 6a,6adicarbonyldioxybis-7,8-didehydro-4,5a- 40 3 84 g 35-89740 mm Hg 23% A,73% B I and 3% DMF epoxy-l7-methylmorphinan, mp. 230-240, [04],, 364 (00.97, MeOH). Analysis Calcd. for C i-1 N 0 (622.65): C, 69.44;

H, 5.50; N, 4.50. Found: c, 69.26;H,;5.64;' N, 4.25 A=NNdimethylfomamide tbmylmethylacetal 4 53.2 g. Ell-93 740 mm Hg B, andtrace of DMF EXAMPLE 23 B N,N-dimethylformamide di-t-butyl acetal Vaporphase chromatography (glc) was performed Preparation of t butyl phenylether on a Hewlett-Packard Model 5750 gas chromato- A mixture of 2.35 g.of phenol and l 0.2 g. of N,N- graphic unit with thermal conductivitycells and helium dimethylformamide di-t-butylacetal was heated at 100 asthe carrier gas. A 6 ft. X 0.25 inch stainless steel colfor 3 h urs u dg n, du ng which time a 9. umn of 5 percent SE-3O on 100-120 meshAW-DMCS solution was obtained. Then an additional 5.1 g. of chromo b Wwas used with a helium flow rate of 67 N,N-dimethylformamide di-t-butylacetal was added cc/min, The oven temperature was programmed at 10 andthe heating was continued for 2 hours. The cooled per minute from 50150.The retention time of N,N- reaction mixture was diluted with ether (300ml.) and dimethylformamide di-t-butyl acetal was 7.2 minutes. washedsuccessively with 2N sodium hydroxide (2 X Thus, 53.2 g, (52 percent) ofN,N-dimethylformamide 100 ml.) and water (2 X 100 ml.). The etherealsolution di-t-butyl acetal of high quality (98 percent pure) was wasdried and concentrated to give 2.27 g. (61 percent) obtained.

of crude t-butyl phenyl ether which after Kugelrohr distillation (10mmHg) gave 1.45 g. (39 percent) of t- EXAMPLE 26 butyl phenyl ether, bp71/ll mm.). Preparation of salicylic acid acetate t-butyl ester fromAnalysis Calcd. for C H 0 (150.21 C, 79.96; H, acetylsalicylic acidFound: 79'78; A mixture of 2.2 g. of acetylsalicylic acid and 5.1 g.EXAMPLE 24 of N,N-dimethylformamide di-t-butyl acetal was stirred 65 atroom temperature for 30 minutes under nitrogen, Preparanon of t'butyll'naphthy] fither during which time a clear solution was obtained. The

A mixture of 3. 6 g. of l-naphthol and 10.2 g. of N,N- reaction mixturewas diluted with chloroform ml.) dimethylformamide di-t-butyl acetal washeated at 100 and washed successively with 2N sodium hydroxide (3 X 75and Water X 50 m h 'm 111- I dimethylformamide dimethyl acetal withtertiary butation was dried and n e e to give no], wherein said acid isa stcrically, highly hindered percent) of crude salicylic acid acetatet-butyl ester. phenol, the Simultaneous removal of the formed Foranalysis, a sample of this salicylic acid acetate tmethanol whereb a ysubstantially pure N,N-d1mcthyl butyl ester was recrystallized fromether, mp 46-47.5. 5 formamide di t butyl aceta] is obtained.

Analysis Calcd. for G i-1 0 (236.26): C, 66.09; H,

Found. C 65 H 656. 2. A process in accordance with claim 1, wherein thew claim; 7 acid catalyst is 2,4,6-tri-t-butyl phenol. 1. Aprocess for thpreparation f b i ll pure 3. A process in accordance with claim 1,wherein the N,N-dimethylformamide di-t-butyl acetal, which com- 10 acidcatalyst is 2,6-di-t-butyl phenol. prises the acid-catalyzedtrans-acetalization of N ,N- I

1. A PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PUREN,NDIMETHYLFORMAMIDE DI-T-BUTYL ACETAL, WHICH COMPRISES THEACID-CATALYZED TRANS-ACETALIZATION OF N,N-DIMETHYLFORMAMIDE DIMETHYLACETAL WITH TERTIARY BUTANOL, WHEREIN SAID ACID IS A STERICALLY, HIGHLYHINDERED PHENOL, AND THE SIMULTANEOUS REMOVAL OF THE FORMED METHANOL,WHEREBY SUBSTANTIALLY PURE N,N-DIMETHYLFORMAMIDE DI-T-BUTYL ACETAL ISOBTAINED.
 2. A process in accordance with claim 1, wherein the acidcatalyst is 2,4,6-tri-t-butyl phenol.
 3. A process in accordance withclaim 1, wherein the acid catalyst is 2,6-di-t-butyl phenol.